Transcript ppt - Department of Public Health Pharmacology & Tox.

ANTIVIRAL AND ANTIRETROVIRAL DRUGS
University Of Nairobi
Department Of Public Health, Pharmacology & Toxicology
JPT 341 Pharmacology &Toxicology
BVM 3RD Year Lecture Notes
Dr Aboge, G.O. BVM, Msc, PhD
2014
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Lecture objectives
1. By the end of this lecture the students should be able;
 To give major groups and specific examples of the
antiviral and antiretroviral drugs.
 To describe the mechanisms of action of antiviral
and
antiretroviral
drugs
including
their
pharmacological effects.
 To outline clinical applications the drugs in vet
medicine.
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Lecture outline
• Introduction
• Classification of antiviral and antiretroviral drugs
• Pyrimidine nucleosides analogues: Idoxuridine
• Purine nucleosides analogues: Acyclovir, Ganciclovir
• Antiviral prodrugs: Ribavirin and Oseltamivir)
• Cyclic amine antiviral drugs: Amantadine
• Antiretrovirals: azidothymidine,
• Biologic Response Modifiers: Interferon, cytockines.
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Introduction
• Antiviral and antiretroviral agents are compounds active
against viruses including retroviruses.
• Since viruses are obligate intracellular microorganisms,
drugs that target viral processes must penetrate host cells.
• Therefore, drugs that negatively impact on a virus are also
likely to negatively impact normal pathways of the host.
• Consequently, antiviral drugs have a narrow therapeutic
margin as compared to antibacterial drugs.
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Classification of antifungal drugs
• Based on chemical structures: The classes include
pyrimidine nucleosides, purine nucleosides analogues and
antimetabolites prodrugs.
• Based on their modification of host biological
functions: Biologic Response Modifiers like cytokines
• Based on the type of viruses they act on: DNA based
viruses or RNA based retroviruses
• Miscellaneous antiviral drugs
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Pyrimidine nucleosides analogues
• Pyrimidine nucleoside analogues mimics pyrimidine
nucleosides in their chemical structures and includes
Idoxuridine and Trifluridine.
Pyrimidine nucleosides Deoxythymidine analogues
Deoxythymidine
Idoxuridine
Trifluridine
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Mechanisms of actions of idoxuridine and trifluridine
• The pyrimidine nucleosides analogues substitute
pyrimidine for thymidine, causing defective DNA
molecules.
• In particular, idoxuridine inhibits viral replication by
substituting itself for thymidine in viral DNA.
• This in turn inhibits the functions of thymidylate
phosphorylase and viral DNA polymerases resulting in
inability of the virus to reproduce and infect tissue.
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Mechanisms of action of idoxuridine and trifluridine
• The mechanism of action of trifluridine has not been
fully determined, but is thought to inhibit viral
replication.
• It does this by incorporating into viral DNA during
replication and forms defective proteins and cause an
increased mutation rate.
• This drug also reversibly inhibits thymidylate synthetase,
an enzyme that is necessary for DNA synthesis.
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Clinical applications of idoxuridine and trifluridine
• Idoxuridine is effective against herpesvirus infection of
the superficial layers of the cornea (herpesvirus
keratitis) and of the skin, but is toxic when administered
systemically.
• Trifluridine is the agent of choice for the treatment of
herpesvirus keratitis in humans.
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Purine nucleosides analogues
• These purine nucleoside analogues mimics guanosine
nucleosides in their chemical structures and includes
vidarabine acyclovir, and ganciclovir.
Guanosine
Ganciclovir
Acyclovir,
vidarabine
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Mechanisms of actions
• Vidarabine is phosphorylated by cellular kinases to a
triphosphate compound, which is an inhibitor and a
substrate of viral DNA polymerase.
• When used as a substrate for viral DNA polymerase, the
phosphrylated compound competitively inhibits dATP
leading to the formation of ‘faulty’ DNA.
• This results in the prevention of DNA synthesis, as
phosphodiester bridges can longer to be built,
destabilizing the strand
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Mechanisms of actions
• Acyclovir is phosphorylated by virus-induced thymidine
kinase to the triphosphate form, which is a better
substrate and inhibitor of viral DNA polymerase,
compared with host.
• Binding to DNA polymerase is irreversible and once
incorporated into viral DNA, the DNA chain is
terminated.
• The mechanism of action of ganciclovir is similar to that
of acyclovir.
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Clinical applications
• Herpesviral enzymes are ~20-fold more susceptible
vidarabine compared with host DNA.
• Vidarabine is effective against chickenpox - varicella,
herpes zoster and herpes simplex.
• Acyclovir is useful against the herpesvirus family and is
available as an ophthalmic ointment, a topical ointment
and cream, an IV preparation, and oral formulations.
• Ganciclovir is effective against human cytomegalovirus.
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Side effects
• Ganciclovir use may cuase neutropenia and
thrombocytopenia, fever, rash, GIT symptoms, confusion
and seizure.
• Vidarabine may cause bone marrow suppression and
CNS problems when high blood levels are reached.
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Antiviral prodrugs
• Ribavirin is a synthetic triazole nucleoside while is
Oseltamivir an acetamido cyclohexene that is analogue
of sialic acid
Oseltamivir
Ribavirin
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Mechanism of action of ribavirin
• Ribavirin is readily phosphorylated intracellularly by
adenosine kinase to ribavirin triphosphate.
• Ribavirin triphosphate is a potent competitive inhibitor
of inosine monophosphate (IMP) dehydrogenase, viral
RNA polymerase and viral mRNA guanylyltransferase.
• Guanylyltranserase inhibition stops the capping of
mRNA
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Mechanism of action of ribavirin
• This causes a marked reduction of intracellular guanosine
triphosphate pools and inhibition of viral RNA and
protein synthesis.
• Ribavirin is also incorporated into the viral genome
causing lethal mutagenesis and a subsequent decrease in
specific viral infectivity.
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Clinical uses of ribarivin
• Ribavirin has a broad spectrum of activity against many
RNA and DNA viruses.
• It is active against adenoviruses, herpesviruses,
orthomyxoviruses,
paramyxoviruses,
poxviruses,
picornaviruses,
rhabdoviruses,
rotaviruses,
and
retroviruses.
• Ribavirin does not have a wide margin of safety in
domestic animals
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Mechanism of action of oseltamivir
• Oseltamivir is hydrolysed to oseltamivir carboxylate, the
active form, which inhibits influenza virus neuraminidase
and thus may alter virus particle aggregation and release.
• Oseltamivir (Tamiflu) is effective against influenza
infection in and has been used for the prophylaxis of
influenza in humansr
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Cyclic amine antiviral drugs
• Amantadine and rimantadine, are cyclic amine antiviral
drugs.
Amantadine
Rimantadine
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Mechanisms of actions of cyclic amine antiviral drugs
• Amantadine drug interferes with a viral protein, M2
(an ion channel needed for the viral particle to become
"uncoated" once it infects the cell.
• This leads to inhibition or delay of the uncoating
process that precedes primary transcription.
• Amantadine may also interfere with the early stages of
viral mRNA transcription.
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Mechanisms of actions of cyclic amine antiviral drugs
• The mechanism of action of rimantadine is not fully
understood.
• It appears to exert its inhibitory effect early in the viral
replicative cycle, possibly inhibiting the uncoating of
the virus.
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Indications and side effects of amantadine
• Amantadine at usual concentrations inhibits replication
of influenza A and C viruses, Sendai virus, and
pseudorabies virus.
• It is used clinically to prevent infection with various
strains of influenza A viruses.
• It produces few adverse effects, related to the CNS
including stimulation of the CNS at very high doses.
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Antiretroviral drugs
• Antiretroviral drugs are medications for the treatment of
infection by retroviruses, primarily HIV.
Thymidine analogue
Azidothymidine, AZT
Synthetic nucleoside
analogue
Lamivudine
Synthetic purine
derivative
Efavirenz
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Mechanisms of actions of antiretroviral drugs
• Generally, antiretroviral drugs inhibits retroviral reverse
transcriptase and subsequent DNA transcription in host
cells preventing viral replication.
• In particular, AZT inhibits viral reverse transcriptase,
which converted the viral RNA into double-stranded
DNA before it is integrated into the host cell genome and
prevents viral replication.
• Efavirenz also inhibits the activity of viral reverse
transcriptase
but the drug must be converted
intracellularly to the active triphosphorylated form. 25
Clinical use of antiretroviral drugs
• These drugs are mainly used in management of HIV and
are of limited use in veterinary medicine
• The drugs are effective for acute infections but are
relatively ineffective for chronically infected cells
because they inhibit early viral replication.
• Granulocytopenia and anemia are the major adverse
effects of AZT in human patients
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Biologic response modifiers
• Biologic response modifiers include cytokines such as;
Interferons (IFN),
Interleukins (IL),
Hematopoietic growth factors
• Recombinant Interferon Alfa-2a has been produced
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Mechanisms of actions of interferon 2α
• Interferons modulate the host immune response and
thus may help in fighting viral infections.
• They bind to receptors on other cells and induce
antiviral proteins that protect the cell from infection.
• IFNs also have antitumor, antiparasitic, and immunomodulatory effects.
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Clinical application of BRM
• Recombinant Interferon Alfa-2a may be used for
treatment of chronic hepatitis C, and oral warts arising
from HIV infection.
• In veterinary medicine, Interferon α-2 (3 × 106 IU/vial)
may used to manage feline leukemia virus, feline
infectious peritonitis and feline immunodeficiency virus.
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References
• Clinical Pharmacology, D.R. LAURENCE & P.N.
BENNET
• Veterinary Applied Pharmacology and Therapeutics
• The Merck Veterinaty Manual
• DrugBank: http://www.drugbank.ca/drugs/
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